Microfluidic combinatorial chemistry

Microfluidic combinatorial chemistryPaul Watts� and Stephen J Haswell

Microreactors are finding increasing application in the field of

combinatorial chemistry. In the past few years, microreactor

chemistry has shown great promise as a novel method on which

to build new chemical technology and processes. It has been

conclusively demonstrated that reactions performed within

microreactors invariably generate relatively pure products in high

yield. One of the immediate and obvious applications is therefore

in combinatorial chemistry and drug discovery.

AddressesDepartment of Chemistry, University of Hull, Cottingham Road,

Hull, HU6 7RX, UK�e-mail: [email protected]

Current Opinion in Chemical Biology 2003, 7:380–387

This review comes from a themed issue on

Combinatorial chemistry

Edited by Samuel Gerritz and Andrew T Merritt

1367-5931/03/$ – see front matter� 2003 Elsevier Science Ltd. All rights reserved.

DOI 10.1016/S1367-5931(03)00050-4

AbbreviationsDBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC N,N-dicyclohexylcarbodiimide

DMF dimethylformamide

EOF electroosmotic flow

IntroductionMicroreactors consist of a network of micron-sized chan-

nels (typical dimensions are in the range 10–300 mm)

etched into a solid substrate (see, for example, [1–9]

for introductory overviews). They may be fabricated from

a range of materials including glass, silicon, quartz, metals

and polymers using a variety of fabrication techniques

including photolithography, hot embossing, powder blast-

ing, injection moulding and laser microforming [10]. For

glass microreactors, photolithographic fabrication of chan-

nel networks is performed as shown schematically in

Figure 1 [11,12].

For solution-based chemistry, the channel networks are

connected to a series of reservoirs containing chemical

reagents to form the complete device with overall dimen-

sions of a few centimetres, as illustrated in Figure 2.

Reagents can be brought together in a specific sequence,

mixed and allowed to react for a specified time in a

controlled region of the channel network using either

electrokinetic (electroosmotic and electrophoretic) or

hydrodynamic pumping. For electrokinetically driven

systems, electrodes are placed in the appropriate reser-

voirs to which specific voltage sequences can be delivered

under automated computer control [13–16]. This control

offers a simple but effective method of moving and

separating reactants and products within a microreactor,

without the need for moving parts. In comparison, hydro-

dynamic pumping uses conventional or microscale pumps

(notably syringe pumps) to manoeuvre solutions around

the channel network; however, this technique has the

disadvantage of requiring either large external pumps or

complex fabrication of small moving parts.

A concerted effort has now begun to establish the benefits

that microreactors can bring to the field of reaction

chemistry. For example, the ability to manipulate reagent

concentrations in both space and time within the channel

network of a microreactor provides an additional level of

reaction control that is not attainable in bulk stirred

reactors, where concentrations are generally uniform

[17��]. Consistent with this notion, many reactions have

been demonstrated to show altered reactivity, product

yield and selectivity when performed in microreactors as

compared with conventional bench-top glassware [18��].

To date, the outcome of the reported research has con-

firmed that microreactor methodology is applicable to

performing both gas- and liquid-phase reaction chemistry

[18��]. From the work cited in this article, the evidence is

that the unique modus operendi of microreactors, namely

the low-volume spatial and temporal control of reactants

and products in a laminar flow diffusive mixing environ-

ment in which distinct thermal and concentration gradi-

ents exist, offers a novel method for the chemical

manipulation and generation of products. In short, micro-

reactors are new, safe and more atom-efficient tools with

which to generate molecules and increase our knowledge

of complex chemical processes.

Reactions performed in microreactorsMost reactions that have been performed in microreactors

have been conducted simply to demonstrate proof of

principle. A summary of the reactions that have been

performed in microreactors to date is presented in Table 1

and these are reviewed in detail in [18��].

This section reviews reactions that have been performed

within microreactor systems specifically with combina-

torial applications.

Skelton and co-workers [19�,20�] have reported the appli-

cation of microreactors, prepared from borosilicate glass,

for the Wittig reaction. They used the microreactor to

380

Current Opinion in Chemical Biology 2003, 7:380–387 www.current-opinion.com

prepare the cis- and trans-nitrostilbene esters 1 and 2 using

the Wittig reaction (Figure 3a). Several features such as

stoichiometry and stereochemistry were investigated.

When two equivalents of the aldehyde 3 to the phospho-

nium salt 4 were used in the reaction, a conversion of 70%

was achieved. The microreactor demonstrated an

increase in reaction efficiency of 10% over the traditional

batch synthesis. The reaction stoichiometry was subse-

quently reduced to 1:1, but using continuous flow of

reagents, as above, the conversion was poor (39%). The

conversion was increased to 59% using an ‘injection’

technique, where ‘slugs’ of 4 were injected into a con-

tinuous flow of the aldehyde 3.

The research was further extended to investigate the

stereochemistry of the reaction. The ratio of isomers 1and 2 was controlled by altering the voltages applied to

the reagent reservoirs within the device, which in turn

affected the electroosmotic flow (EOF) and electrophore-

tic mobility of the reagents. The variation in the external

voltage subsequently altered the relative reagent concen-

tration within the device, producing Z/E ratios in the

region 0.57–5.21. In comparison, the authors report that

when a traditional batch synthesis was performed using

the same reaction time, concentration, solvent and stoi-

chiometry, a Z/E ratio of approximately 3:1 was observed.

This demonstrated that significant control was possible in

a microreactor compared with batch reactions. The

authors also demonstrated that the microreactor could

to used as a tool for the rapid reaction development and

optimisation based on analogue chemistry by using other

aldehydes in the reaction [19�,20�].

Carbanion chemistry is one of the most common methods

of C–C bond formation used in the pharmaceutical

industry. The temperature of the reaction often governs

the stereochemistry of the product, hence microreactors

have a considerable attraction because the reactor

enables excellent temperature control to be attained.

Wiles et al. [21�] have recently demonstrated the use

of silyl enol ethers in the aldol reaction within a micro-

reactor. Quantitative conversion of the silyl enol ethers to

Figure 1

PhotoresistMask

Metal layer

Photoresist exposedto light through mask

•

Top block thermally bondedto form microchannel

•

Photoresist andmetal removed

•

Exposed glassetched

•

Photoresist developedand exposed metaletched

•

Current Opinion in Chemical Biology

Photolithographic fabrication of microreactors.

Figure 2

A borosilicate glass microreactor.

Microfluidic combinatorial chemistry Watts and Haswell 381

www.current-opinion.com Current Opinion in Chemical Biology 2003, 7:380–387

Table 1

Reactions conducted in a microreactor.

Reaction Chip material Solvent Conversion (%) Comments Refs

Suzuki Glass Aq THF 67 EOF [28]Kumada coupling Polypropylene THF 60 Syringe pump [29]

Nitration Glass Benzene 65 EOF [30]

Enamine Glass MeOH 42 EOF [31]

Diazo coupling Glass MeOH 37 EOF [32]

MeCN 22

Diazotisation Glass DMF/H2O 52 Syringe pump [33]

Photocyanation Polymer Pyrene/H2O 73 Syringe pump [34]

Dehydration Glass/PDMS EtOH 85–95 EOF or syringe pump [35]

Esterification Glass/PDMS EtOH 30 Syringe pump [36]

Photochemical Silicon/quartz (CH3)2CHOH 60 Syringe pump [37]

Photochemical Glass MeOH 80 Syringe pump [38]

Phase transfer Glass EtOAc 100 Syringe pump [39]

Fluorination Ni or Cu Nitrogen gas 90–99 Syringe pump [40,41]

Fluorination Silicon/Pyrex MeOH 80 Syringe pump [42]

Oxidation Al None 75–99 Syringe pump [43]

Figure 3

PPh3.Br

NO2

CHO

CO2Et NO2CO2Et

NO2

CO2Et

4 3

OTMS

5

O

6

−O

Br

OH

8

OHC

Br

R R′ R R′

O O

EtO O10 R = Ph; R′ = Me11 R = Me; R′ = Me

12 R = Ph; R′ = Me13 R = Me; R′ = Me

EtO

O

9

iPr2EtN

1

2

+

+ NaOMe

MeOH

(a)

(b)

TBAF

THF

(c)

O O


7

Reactions performed within microreactors. (a) The Wittig reaction. (b) The aldol reaction. (c) Michael addition.

382 Combinatorial chemistry


b-hydroxyketones was observed in 20 min in the micro-

reactor, compared with traditional batch systems where

quantitative yields were only obtained when extended

reaction times of up to 24 h were employed. One example

involved the treatment of the trimethylsilyl enol ether 5with tetra-n-butylammonium fluoride (TBAF), to gener-

ate the tetra-n-butylammonium enolate 6 in situ, followed

by condensation with p-bromobenzaldehyde 7 to give the

b-hydroxyketone 8 in 100% conversion (Figure 3b). The

reaction has also been successfully achieved using a

variety of other silyl enol ethers and aldehydes, which

demonstrates that microreactors may be used in the

synthesis of combinatorial libraries.

Similarly, Wiles et al. [22�] have also reported the pre-

paration of the enolates from a series of 1,3-diketones

using an organic base and their subsequent reaction with a

variety of Michael acceptors such as 9 to afford 1,4-

addition products within a microreactor (Figure 3c).

When using a continuous flow of reagents 9 and 10, 15%

conversion to the adduct 12 was observed, compared with

56% when the diketone 11 was reacted with 9 forming the

Michael adduct 13. The authors, however, demonstrated

enhancements in conversions through the application of

the stopped-flow technique. This procedure involved the

mobilisation of reagents through the device for a desig-

nated period of time, using an applied field, and the flow

was subsequently paused by the removal of the applied

field, before re-applying the field. Using the regime of

2.5 s on and 5 s off, the conversion to the product 12 was

improved to 34%, whereas lengthening the stopped-flow

period to 10 s, resulted in a further increase to 100%. This

was compared to the preparation of 13, in which the

regime of 2.5 s on and 5 s off resulted in an increase in

conversion to 95%. This demonstrated that the enolate of

2,4-pentanedione 11 was more reactive than the corre-

sponding enolate of benzoyl acetone 10. The authors

propose that the observed increase in conversion, when

using the technique of stopped flow, was due to an

effective increase in residence time within the device

corresponding to the different kinetics associated with

these reactions. This approach is clearly relevant to those

wishing to study the kinetics of such reactions and the

results demonstrate the ease with which reactions may

be optimised in microreactors when conducting com-

binatorial synthesis.

Although the previous result demonstrates the ease with

which reaction conditions may be optimised, it is still

sometimes necessary to heat reactions to achieve high

yields of products. Industrially, special equipment is

required when performing large-scale reactions at ele-

vated temperature. However, Garcia-Egido et al. [23��]have demonstrated the synthesis of a series of 2-ami-

nothiazoles using a Hantzsch synthesis within a micro-

reactor. The paper represents the first example of a

heated solution-based organic reaction within a glass

microreactor under EOF conditions. The T-shaped

microreactor was heated to 708C using a Peltier heater,

which was aligned with the channels, and the heat gen-

erated by the device was applied to the base of the

microreactor. Reaction of a-bromoketones such as 14with a thiourea derivative such as 15, using N-methyl-

pyrrolidinone as solvent, resulted in the preparation of the

aminothiazoles 16 in up to 85% conversion (Figure 4a).

Fernandez-Suarez et al. have reported the synthesis of

cycloadducts in a microreactor using hydrodynamic dri-

ven flow [24�]. The reactions consisted of Knoevenagel

condensation of an aldehyde 17 with a 1,3-diketone 18with ethylenediamine acetate (EDDA) as catalyst, in

aqueous methanol as solvent. The reaction intermediate

underwent an intramolecular hetero-Diels-Alder reaction

to form cycloadduct 19 in 60–68% conversion (Figure 4b).

Initially, four different compounds were prepared indi-

vidually but the research was extended to a multi-reaction

experiment where all compounds were prepared in a

single run.

Watts et al. [25,26��] have recently demonstrated the first

example of a multi-step synthesis in a microreactor, using

their devices in peptide synthesis. The authors evaluated

the reactor using a carbodiimide coupling reaction of

Fmoc-b-alanine 20 with the amine 21 to give the dipep-

tide 22 (Figure 4c). When stoichiometric quantities of the

reagents were used, only ca 10% conversion to dipeptide

22 was achieved. By using two equivalents of N,N-dicy-

clohexylcarbodiimide (DCC), however, an increase in

conversion to ca. 20% was observed, and by applying a

stopped flow technique (2.5 s injection length with stopped

flow for 10 s) the conversion of the reaction was further

increased to approximately 50%. Using five equivalents of

DCC, a conversion of up to 93% of 22 was obtained using

the stopped-flow technique.

The authors also demonstrated that the dipeptide could

be prepared from pre-activated carboxylic acids [25,26��].They reported that the reaction of the pentafluorophenyl

(PFP) ester of Fmoc-b-alanine 23 with the amine 21 gave

the dipeptide 22 quantitatively in 20 min (Figure 4d).

This represented a significant increase in yield compared

with the traditional batch synthesis, where only a 50%

yield was obtained in 24 h.

Having demonstrated that peptide bonds could be suc-

cessfully formed when using a microreactor, the authors

then found that they could extend the methodology

to the preparation of longer-chain peptides. Using the

microreactor, the Dmab ester of Fmoc-b-alanine 24was reacted with one equivalent of piperidine or 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) to give the free

amine 21 in quantitative conversion. This is in compar-

ison with solid-phase peptide synthesis where 20%



piperidine in dimethylformamide (DMF) is frequently

employed, which demonstrates the atom efficiency of

reactions performed within the devices. The authors then

reacted the amine in situ with the pentafluorophenyl ester

25 to give the dipeptide 26 (Figure 5a) in 96% overall

conversion.

Having shown that more complex peptides could be

produced by removal of the N-protecting group, the

authors then demonstrated that they could remove the

Dmab ester using hydrazine. The reaction of the Dmab

ester 24 with one equivalent of hydrazine resulted in

quantitative deprotection, to afford the carboxylic acid 20(Figure 5b). This is in comparison to solid-phase peptide

synthesis where 2% hydrazine in DMF is generally

required to effect complete deprotection.

The authors have further extended the approach to the

synthesis of tripeptide 28 [26��]. Reaction of pentafluoro-

phenyl ester 23 with amine 21 formed dipeptide 22,

which was reacted with DBU to effect Fmoc deprotec-

tion. The amine 27 was then reacted in situ with another

equivalent of pentafluorophenyl ester 23 to prepare tri-

peptide 28 in 30% overall conversion (Figure 5c). The

approach clearly demonstrates that intermediates may be

generated in situ and used in subsequent reactions,

enabling the combinatorial synthesis of peptides, which

are of biological and pharmaceutical interest.

Having demonstrated that peptide bonds could be suc-

cessfully formed when using a microreactor, the authors

then investigated racemisation in peptides derived from

a-amino acids [27]. Reaction of the pentafluorophenyl

ester of R-2-phenylbutyric acid 29, at 0.1 M concentra-

tion, with a-methylbenzylamine 30, gave the product 31in quantitative conversion with 4.2% racemisation

(Figure 5d). Importantly, there was less racemisation than

observed in the batch reaction at the same concen-

tration and temperature. The reduced level of racemisa-

tion was attributed to the reduced reaction times

observed within the microreactors. This demonstrates

that there would be real advantages to performing com-

binatorial chemistry in microfluidic reactors compared

with traditional batch systems.

Figure 4

Br

O

NH

NH2

SO

NH

S

NO

H

O

N

N

O

OO

O N

N

O

O

H

H

14 15+

16

17

EDDA

19

FmocHN OH

O H2N ODmab

O

20

21

DCC, DMF

FmocHNH

O

22

ODmab

O

FmocHN OPFP

OH2N ODmab

O

FmocHH

O

ODmab

O

23

21

DMF 22

(a)

(b)

+

(c)

N

18

N

(d)


Reactions performed within microreactors. (a) Hantzsch reaction. (b) Cycloadduct formation. (c,d) Peptide bond formation reactions.



ConclusionsMicroreactor chemistry is currently showing great pro-

mise as a novel method on which to build new chemical

technology and processes. Reactions performed in a

microreactor invariably generate relatively pure products

in high yield, in comparison to the equivalent bulk

reactions, in much shorter times and in sufficient quan-

tities to perform full instrumental characterisation. One of

the immediate and obvious applications is therefore in

combinatorial chemistry and drug discovery, where the

generation of compounds either with different reagents or

under variable conditions is an essential factor. An inter-

esting twist to the chemistry carried out to date is not just

the opportunity to separate reactants and products in real

time but also the capability to manufacture and use

reagents in situ.

The success of pharmaceutical companies resides largely

on the ability to synthesise novel chemical entities and to

optimise the production of marketable drugs. In an

Figure 5

FmocHN ODmab

O

24

DBU

DMFH2N ODmab

O

21

BocHN OPFP

O

25DMF

BocHN

O

26

ODmab

O

FmocHN ODmab

O

24

FmocHN OH

O

20

NH2NH2

DMF

FmocHN OPFP

O

23

H2N ODmab

O

21FmocHN N

H

O

22ODmab

O

DBU

FmocHN NH

O

NH

O

28

ODmab

OFmocHN OPFP

O

23

H2 N NH

O

27

ODmab

O

OPFP

O

Ph29

H2 Ph

Me30

NH

O

Ph31

Ph

Me

(a)

NH

(b)

(c)

(d)

N


Peptide synthesis within microreactors.



industry where development costs are extraordinarily

high and attrition rates from lead generation onwards

are about 98%, careful lead selection and ruthless pres-

sure to shorten optimisation times are crucial for survival,

microreactor technology could certainly help meet these

criteria.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest��of outstanding interest

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16. Jednacak J, Pravdic V, Haller W: The electrokinetic potential ofglasses in aqueous electrolyte solutions. J Colloid Interface Sci1974, 49:16-23.

17.��

Fletcher PDI, Haswell SJ, Zhang X: Electrokinetic control of achemical reaction in a lab-on-a-chip micro reactor:measurement and quantitative modelling. Lab on a Chip 2002,2:101-112.

This paper demonstrates the spatial and temporal control achievablewhen performing a reaction in a microreactor under electrokinetic flow.Specifically, Ni2þ ions are reacted with a ligand to produce a complex.The results demonstrate that Ni2þ ions have a greater electrophoreticvelocity than the neutral ligand.

18.��

Fletcher PDI, Haswell SJ, Pombo-Villar E, Warrington BH,Watts P, Wong SYF, Zhang X: Micro reactors: principles andapplications in organic synthesis. Tetrahedron 2002,58:4735-4757.

This review article gives a detailed account of the fabrication and opera-tion of microreactors. The paper gives a detailed account of all gas phase,liquid phase and catalysed reactions performed in microreactors to date.

19.�

Skelton V, Greenway GM, Haswell SJ, Styring P, Morgan DO,Warrington B, Wong SYF: The preparation of a series ofnitrostilbene ester compounds using micro reactortechnology. Analyst 2001, 126:7-10.

This paper uses a borosilicate glass microreactor, operating underelectrokinetic control, to prepare a range of stilbenes using the Wittigreaction. A range of starting materials are used, demonstrating that it ispossible to prepare a combinatorial library of derivatives using themicroreactor systems.

20.�

Skelton V, Greenway GM, Haswell SJ, Styring P, Morgan DO,Warrington B, Wong SYF: The generation of concentrationgradients using electroosmotic flow in micro reactors allowingstereoselective chemical synthesis. Analyst 2001, 126:11-13.

This paper uses a borosilicate glass microreactor, operating underelectrokinetic control, to prepare stilbenes using the Wittig reaction. Itdiscusses how the Z/E ratio of isomers changes depending on theelectrokinetic parameters used.

21.�

Wiles C, Watts P, Haswell SJ, Pombo-Villar E: The aldol reactionof silyl enol ethers within a micro reactor. Lab on a Chip 2001,1:100-101.

This paper illustrates how a selection of enolates may be prepared in situwithin microreactor devices. The enolates are subsequently reacted witha range of aldehydes to form a variety of aldol products in high yield.

22.�

Wiles C, Watts P, Haswell SJ, Pombo-Villar E: 1,4-Addition ofenolates to a,b-unsaturated ketones within a micro reactor.Lab on a Chip 2002, 2:62-64.

This paper prepares a range of Michael adducts by reaction of a selectionof diketones with an organic base in a microreactor. The paper illustratesthat microreactors may be used to study the kinetics of reactions.

23.��

Garcia-Egido E, Wong SYF, Warrington BH: Synthesis of athree-member array of cycloadducts in a glass microchipunder pressure driven flow. Lab on a Chip 2002, 2:170-174.

This paper demonstrates that an array of compound may be simulta-neously produced within microreactor devices operating under pressure-driven flow. This methodology may be used for a combinatorial library ofcompounds.

24.�

Fernandez-Suarez M, Wong SYF, Warrington BH: A Hantzschsynthesis of 2-aminothiazoles performed in a heatedmicroreactor system. Lab on a Chip 2002, 2:31-33.

This paper reports a convenient method of heating a reaction in amicroreactor by aligning a Peltier heating device with the fluidic channels.It is demonstrated how such devices may be applied to combinatorialchemistry.

25. Watts P, Wiles C, Haswell SJ, Pombo-Villar E, Styring P: Thesynthesis of peptides using micro reactors. Chem Commun2001:990-991.

26.��

Watts P, Wiles C, Haswell SJ, Pombo-Villar E: Solution phasesynthesis of b-peptides using micro reactors. Tetrahedron 2002,58:5427-5439.

This paper illustrates that a series of peptide derivatives may be preparedin situ within microreactor devices. The methodology has been extendedsuch that tripeptides may be prepared by careful control of protecting-group chemistry. The paper illustrates that reactions in microreactors areconsiderably faster than in batch reactions and an electrochemical effectis reported.

27. Watts P, Wiles C, Haswell SJ, Pombo-Villar E: Investigation ofracemisation in peptide synthesis within a micro reactor.Lab on a Chip 2002, 2:141-144.

28. Greenway GM, Haswell SJ, Morgan DO, Skelton V, Styring P:The use of a novel microreactor for high throughput continuousflow organic synthesis. Sens Actuators B Chem 2000,63:153-158.

29. Haswell SJ, O’Sullivan B, Styring P: Kumada-Corriu reactions in apressure-driven microflow reactor. Lab on a Chip 2001,1:164-166.

30. Doku GN, Haswell SJ, McCreedy T, Greenway GM: Electricfield-induced mobilisation of multiphase solution systemsbased on the nitration of benzene in a micro reactor.Analyst 2001, 126:14-20.

31. Sands M, Haswell SJ, Kelly SM, Skelton V, Morgan DO, Styring P,Warrington BH: The investigation of an equilibrium dependentreaction for the formation of enamines in a microchemicalsystem. Lab on a Chip 2001, 1:64-65.



32. Salimi-Moosavi H, Tang T, Harrison DJ: Electroosmotic pumpingof organic solvents and reagents in microfabricated reactorchips. J Am Chem Soc 1997, 119:8716-8717.

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34. Ueno K, Kitagawa F, Kitamura N: Photocyanation of pyreneacross an oil/water interface in a polymer microchannel chip.Lab on a Chip 2002, 2:231-234.

35. WilsonNG,McCreedyT:On-chipcatalysis usinga lithographicallyfabricated glass microreactor-the dehydration of alcohols usingsulfated zirconia. Chem Commun 2000:733-734.

36. McCreedy T, Wilson NG: Microfabricated reactors for on-chipheterogeneous catalysis. Analyst 2001, 126:21-23.

37. Lu H, Schmidt MA, Jenson KF: Photochemical reactions andon-line UV detection in microfabricated reactors. Lab on a Chip2001, 1:22-28.

38. Wootton RCR, Fortt R, de Mello AJ: A microfabricatednanoreactor for safe, continuous generation and use of singletoxygen. Organic Process Res Dev 2002, 6:187-189.

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40. Chambers RD: Spink RCH: microreactors for elemental fluorine.Chem Commun 1999:883-884.

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43. Dietzsch E, Honicke D, Fichtner M, Schubert K: Weibmeier G:The formation of cycloalkenes in the partial gas phasehydrogenation of c,t,t 1,5,9-cyclodecatriene, 1,5-cyclooctadiene and benzene in micro channel reactors.In IMRET 4: Proceedings of the Fourth International Conference onMicroreaction Technology. Edited by Matlosz M, Ehrfeld W,Baselt JP. Berlin: Springer; 2000:89-93.



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